The subject of the present invention is the use of defined guanidine compounds as physiological strengthening agents.
Guanidine compounds and especially endogenous guanidine compounds have long been known as appropriate nutritional supplements, feed additives, or as components of cosmetic preparations. Particularly creatine can be mentioned as a representative compound, being an endogenous amino acid derivative which, especially as a phosphocreatine rich in energy, in addition to adenosine triphosphate (ATP), is an important energy reserve of muscle. For creatine can absorb phosphate in an energy-rich bond, and thus is in direct equilibrium with ATP.
Creatine is produced primarily by the liver and kidneys under physiological conditions and is stored in small amounts in muscle tissue where it serves as phosphocreatine in the action state by the above-mentioned phosphate group transfer to ADP for the regeneration of ATP. However, when muscles work hard and over a fairly long time, the creatine supplies naturally present in the body are rapidly exhausted. For this reason, targeted doses of creatine, especially in competitive sport participants, have had a positive effect on their endurance and performance, while undesirable accumulation processes in the body or harmful degradation products are unknown. The reason for this is to be seen in the fact that in the case of any overshooting administration, the creatine is excreted always in the form of physiological creatinine.
In addition to creatine itself, however, i.e., the creatine monohydrate, numerous creatine salts, such as creatine ascorbate, citrate, pyruvate and others, have also proven to be suitable nutritional supplements. Representatives that can be mentioned here are European patent EP 894 083 and German Offenlegungsschrift DE 197 07 694 A1.
The effects which have been produced by creatine in human beings and have proven beneficial are also, however, produced in animals, so that for years its use in various animal feeds have also been prescribed. In International Patent Application WO 00/67 690 the use of creatine or creatine salts as feed additive for breeding animals and fattening animals, as a replacement for animal meal, fish meal and/or antimicrobial performance enhancers, growth hormones, as well as anabolics. GB 2 300 103 teaches the use of creatine in the form of a dog biscuit, for which purpose creatine monohydrate is offered together with meat in an extruded composition. But since creatine monohydrate is only insufficiently bioavailable due to its poor solubility, its use in common with other physiologically active compounds is recommended, preferably in a salt form. The subject of German Offenlegungsschrift DE 198 36 450 A1 is the use of stable pyruvic acid salts and especially creatine pyruvate in formulations which are appropriate for animal nutrition.
In addition to their function as energy reserves and their consequent use as nutritional supplements and animal feed additives, guanidine derivatives, and here again, especially creatine, are suitable also for cosmetic applications. Thus German Offenlegungsschrift DE 198 41 386 describes creatine as a cosmetic moisturizer, the creatine, mainly in the form of cremes, feeding moisture to the upper skin layers in topical applications, with the result of improving tissue turgor and the smoothing of wrinkles.
DE 100 03 835 A1 deals with formulations in dehydration conditions, such as generally occur in older persons and especially those with limited mobility. In this case too, creatine acts as a transport medium for water so as to provide moisture to tissues most severely affected by dehydration symptoms.
In addition to its known properties as a physiological strengthening agent, mainly in infants, in the form of nutritional supplements, animal feed additives or also in cosmetic preparations, creatine is also proposed as a plant growth stimulant (still unpublished).
In addition to its undisputed positive physiological properties, creatine has the disadvantage, however, that it is poorly soluble as creatine monohydrate and has no particular storage ability in the corresponding aqueous solutions, changing to creatinine after a relatively long time.
In the state of the art, in addition to creatine and its derivatives as prominent guanidine compounds, creatinol, which is used mainly in the form of creatinol-O-phosphate as a medicament for strengthening cardiac functions.
Creatinol-O-phosphate is catabolized in the cell to creatinol, while creatinol-O-phosphate, like creatine, is evidently also converted to creatinine. Thus, G. F. Melloni et al. state that the creatinine levels increase in the urine after the administration of creatinol-O-phosphate (in: Arzneimittelforschung 1979, 29 (9A) 1477-79). It is therefore to be assumed that creatinol is first reacted in the cell to creatine in order then to be excreted in the normal way, i.e., also as creatinine.
Creatinol and its salts have previously been described to only a limited extent, GB 1 468 998 and FR 2 162 262 being here named, for example. The British patent describes creratinol derivatives as well as a manufacturing process appropriate for that purpose, and its use in pharmaceutical formulations, which can be administered orally, parenterally or rectally. In experiments performed accordingly on rats a swimming activity increased by 30% could be detected with creatinol aspartate. Usually, creatinol and its appropriate derivatives are mainly used for treating muscular diseases, such as myasthenias, i.e., autoimmune neuromuscular diseases of the skeletal muscles and the heart muscle. The said French patent describes creatinol sulfate and a method of manufacturing it, the compound itself again being used in the treatment of cardiopathies and myasthenias.
In the Chinese patent CN 1 078 364, creatinol is used in conjunction with a principal agent made from morin root in the form of tea for the treatment of senility phenomena, to promote spermatogenesis and to increase kidney tone.
Based on the disadvantages of the state of the art as regards creatine, the problem is created for the present invention of providing guanidine compounds for a new use as physiological strengthening agents. The guanidine compounds to be used are to have but low instability insofar as possible, especially in aqueous solution, and are to be transformed to the corresponding degradation products only after application or physiological absorption. The degradation products formed by catabolic processes are to be kidney-accessible, have no physiologically undesirable effects and be easily detectable. From the economic standpoint it was also important for the guanidine derivatives being used according to the invention to be able to be manufactured in an economically desirable manner.
This problem was solved by the use of guanidine compounds of General Formula (I):

as physiological strengthening agents in the form of nutritional supplements, animal feed additives, or in cosmetic preparations in the non-medicinal field of application, as well as plant stimulants.
It was found surprisingly in their use according to the invention that the claimed compounds actually do satisfy the profile of the requirements that were made, since they can be manufactured in a simple and economical manner; in contrast to creatine and creatine monohydrate, they have a pronounced stability in aqueous solution, and evidently they actually follow the creatine course under physiological conditions. Thus, the guanidine compounds used in connection with the claimed use, and especially the creatinol derivatives, are first converted to creatine in the cell and then are excreted as creatinine. Surprisingly it has proven especially advantageous that the guanidine derivatives described in the present connection, in contrast to creatine, are thus actually transformed under physiological conditions to the particular degradation products, so that the predominant part of the compounds used is not lost by instability reactions in the preliminaries to the known creatine, but are actually available to the physiological areas of application. The guanidine compounds according to the invention can thus be re-used, unlike creatine and its derivatives, to the identical effect, with definitely lower dosages. The advantages of the use claimed by the invention were thus not foreseeable in their entirety.